Acquired Disorders of Coagulation

Either a deficiency (impaired synthesis or Ý loss) or a functional defect (synthetic defect or the presence of an inhibitor)

Vit K deficiency

A fat soluble vitamin that is a co-factor for liver g -carboxylase. g -carboxylase inserts a carboxyl group into glutamic residues of factors II, VII, IX, and X, which is essential to the proper functioning of these factors. Vit K is also needed for modification of anti-coagulant proteins C and S, but the net effect of Vit K deficiency is hemorrhagic.

Causes of Vit K def: ß diet, malabsorption, warfarin, antibiotics, alterations in gut flora.

Diagnosis of Vit K def: Ý PT and PTT corrected with Vit K therapy. Functional assays low, quantitative assays normal. (the factors are there, they’re just not working very well because they haven’t been modified correctly)

Treatment: IV or IM Vit K. For acute correction of plasma coagulation, transfusion of FFP can achieve rapid hemostasis.

Hemorrhagic Disease of the Newborn: due to Vit K deficiency in newborns. Not seen today because each new baby is given a Vit K shot. Babies Vit K stores are low, their GI tracts are sterile, and breast milk doesn’t contain that much. Clinical bleeding is rarely massive, but typically consists of oozing from the umbilical stump, circumcision site, and GI bleeding.

Warfarin, the most commonly used oral anticoagulant, interferes with the Vit K cycle by inhibiting Vit K reductase and Vit K epoxide reductase. Impairment of the reutilization of Vit K results in functional Vit K deficiency. Exposure to warfarin-like compounds in rat poison, or surreptitious abuse of warfarin can lead to severe hemorrhagic manifestations.

Oral antibiotic therapy. Suppression of normal intestinal flora by oral antibiotic therapy may lead to Vit K deficiency by preventing its synthesis by intestinal bacteria. Symptomatic Vit K deficiency usually does not occur unless there also is concomitant poor oral intake of Vit K. This is seen most frequently in the postsurgical patient receiving antibiotics.

Poor absorption of vitamin K. Poor absorption of Vit K from the intestine occurs if there is biliary tract obstruction, pancreatic disease preventing the secretion of lipase, bowel wall disease resulting in malabsorption, or a drug is administered impairing the absorption of bile salts. Patients receiving TPN require Vit K supplementation.

Liver Disease

Since the liver is the main site of synthesis for all coagulation factors (except VIII and vWF), liver disorders lead to bleeding diathesis.

ß synthesis of clotting factors – ß F VII (1^st because of its short T_1/2), ß F V (an indicator of the extent of liver damage), Ý F VIII and vWF, ß Protein C and S, ß ATIII, normal or ß Fibrinogen (ß until late in the disease, a poor P_x sign)

qualitative abnormalities of fibrinogen - Ý PT with normal fibrinogen level. Ý sialic acid results in impaired polymerization.

Increased consumption of coagulation factors – patients with advanced cirrhosis or acute hepatitis have Ý rates of consumption of fibrinogen due to activation of the coagulation cascade, loss into extravascular spaces, activation of the fibrinolytic system, or hemorrhage.

Activation of the fibrinolytic system - Deficiency of the fibrinolytic inhibitors 2-plasmin inhibitor and 2-macroglobulin due to hepatocellular synthetic dysfunction, and increased tPA because of impaired hepatic clearance, lead to excessive generation of plasmin in the circulation. Plasmin degradation of fibrin and fibrinogen generates fibrin(ogen) degradation products (FDPs) and D-dimers. Fibrinolysis may exacerbate bleeding by digesting previously formed clots.

Impaired clearance of coagulation factors. The liver removes activated coagulation factors from plasma, its failure to do so when diseased can initiate or augment DIC. FDPs are cleared improperly in chronic liver failure. Their elevation exacerbates the bleeding in liver disease since FDPs are potent anticoagulants and platelet inhibitors.

Thrombocytopenia and platelet functional defects. ~35% of patients with cirrhosis have thrombocytopenia. The most common cause is portal HTN with resultant hypersplenism. A number of patients with acute and chronic liver disease also have platelet dysfunction. The cause is multifactorial with platelet membrane abnormalities, storage pool-like defects and elevated FDPs contributing to platelet dysfunction.

Labs: Ý PT and PTT, Ý F VIII, Ý Thrombin time, ß platelets, ß Fs V, VII, II, IX, X, ß Fibrinogen, ß Euglobin clot time.

Treatment: FFP, large volumes and frequent transfusions, or Liver transplant.

DIC

An excess production of thrombin that can not be controlled. Excess thrombin Þ excess clotting. Coagulation factors are consumed and bleeding results.

There are two major mechanisms for triggering DIC:

(1) release of tissue factor or thromboplastic substances into the blood. Tissue factor initiates the extrinsic pathway of coagulation and is the common end-point of many DIC-eliciting conditions
(20 Endothelial cell damage ignites DIC by causing release of tissue factor, promoting the aggregation of platelets (due to the exposed subendothelium) and by activating the intrinsic coagulation cascade.

Clinical manifestations DIC typically acute but chronic DIC can occur. The pathologic process is predominantly thrombotic, initial clinical events usually relate to hemorrhage (mucosal oozing, spontaneous ecchymoses, petechiae and GI blood loss). Microcirculatory occlusion can lead to end organ hypoperfusion, ischemia and infarction. The kidney, brain and skin are most often affected. Microangiopathic hemolytic anemia due to shearing of the red blood cells by fibrin deposited in the microvasculature occurs in > 50% of cases. The adrenal cortex may by involved (hemorrhagic necrosisÞ renal insufficiency) in Waterhouse-Friderichsen syndrome.

Labs in DIC: ß platelets, ß ATIII, ß Fibrinogen, ß Euglobin clot time, Ý PT and PTT, Ý FDPs and D-dimers, Ý Thrombin time

Peripheral Blood Smear: Microangiopathic peripheral blood smear with fragmented RBCs.

Things that initiate DIC:

Acute DIC Infections (esp. Gram -, Rocky mnt spt fever, Ebola), Shock, Trauma (esp. head), Burns, Intravascular hemolysis (e.g. ABO incompatibility), Snake bites, Heat stroke, OB complications (e.g. retained dead fetus and amniotic emboli), as well as the LeVeen Shunt procedure which returns TF rich ascites fluid to the vascular space.

*Gram negative sepsis causes release of IL-1 and TNF-a from monocytes in response to endotoxin. These cytokines initiate the expression of Tissue factor by endothelium. In addition endotoxin inhibits the activity of Protein C by inhibiting Thrombomodulin expression, thereby inhibiting protein C activation by thrombin.

Chronic DIC from solid malignancies and Acute Promyelocytic leukemia

Treatment of DIC REMOVE THE UNDERLYING CAUSE! Low dose Heparin, life support measures, Fibrinolytic inhibitors, transfusion support, currently trial with ATIII concentrates.

Immune Coagulation Disorders

Inhibitors of F VIII – most commonly IgG Abs, reacts slowly in vitro (needs hours of incubation)

In patients with Hemophilia A : may develop from exposure to F VIII in blood products. Treatment is challenging. Try porcine F VIII.
Spontaneously acquired F VIII inhibitors: associated with SLE, RA, and post partum. 50% have no association. Clinically a bleeding disorder similar to Hem. A. Treatment is the same. Immunosuppression may be attempted for long term control.

Other Inhibitors - all factors may have inhibitors, F V inh. May occur in surgical patients exposed to bovine thrombin preparations (due to bovine F V in the preparations) the anti-bovine F V Ab may cross react with human F V.

Lupus Anticoagulant – An IgG or IgM Ab against phospholipid seen in SLE, AIDS, autoimmune diseases, certain drugs (phenothiazides) and without any underlying disorder. Ab does not cause bleeding but prolongs PPT and is associated with recurrent spontaneous abortions, intrauterine fetal death, venous and/or arterial thrombosis, and thrombocytopenia. 20% have F II deficiency as well. Treatment of the lupus anticoagulant with immunosuppressive agents in usually effective.

Acquired hemostatic Disorders associated with Paraproteinemias

Hyperviscosity syndrome – patients may develop a bleeding tendency due to Ý serum viscosity although platelet dysfunction and coagulation factor deficiencies may play a role

Inhibitors of Fibrin polymerization - may occur in multiple myeloma. Due to the production of an interfering Ab by the abnormal plasma cells. Major lab feature Ý thrombin time. Occasionally associated with severe clinical bleeding.

Coagulation factor deficiencies due to Ý Clearance Rarely, patients with monoclonal Igs develop Abs that bind a coagulation factor and cause its rapid disappearance from plasma resulting in a factor deficiency.

Coagulation defects associated with amyloidosis Factor X is absorbed by amyloid fibrils and may be cleared rapidly from the plasma leading to a deficiency. Significant bleeding may occur. Less frequently, patients with amyloidosis may develop an acquired deficiency of plasminogen activator inhibitor 1 (PAI-1) with subsequent accelerated fibrinolysis.

Drug-induced coagulopathies

The effects of warfarin and antibiotics have been detailed above. L-asparaginase, a common chemotherapeutic reagent, causes hypofibrinogenemia and deficiencies of other coagulation factors including antithrombin III leading to thrombosis and rarely, hemorrhage.

Hemorrhagic diathesis associated with extracorporeal circulation

Extracoporeal perfusion exposes blood to large surface areas composed of a synthetic polymer lacking an endothelium which activates F XII and the intrinsic coagulation cascade. This necessitates the use of heparin during cardiac bypass. The anticoagulant effects of heparin are carefully monitored during surgery with the activated clotting time (ACT), a measure of the ability of whole blood to clot. Fibrinolysis is also enhanced and platelets are activated by the abnormal substratum and form thromboemboli. Thrombocytopenia and platelet dysfunction typically result. The protease inhibitor, aprotinin, has shown promise in ameliorating the coagulopathy associated with cardiopulmonary bypass probably by inhibiting fibrinolysis.